We have investigated the constitutive expression of a panel of cytokines (interleukin [IL]-2, IL-4, IL-6, IL-10, tumor necrosis factor [TNF]-alpha, and interferon [IFN]-gamma) in sequential peripheral blood mononuclear cell (PBMC) samples from nine individuals with primary human immunodeficiency virus (HIV) infection and three with acute Epstein Barr virus (EBV) infection. IL-2, IL- 4, and IL-6 were minimally expressed or absent in PBMC from patients with both HIV and EBV primary infections. However, substantial levels of IL-2 expression were found in lymph node mononuclear cells (LNMC) of one patient with primary HIV infection. Expression of IL-6 was detected in the PBMCs of three patients with HIV primary infection at a time when downregulation of viremia had already occurred. Expression of IL-10 and TNF-alpha was consistently observed in all patients. However, following the downregulation of viremia a late peak in the expression of these cytokines was observed in four of nine patients with primary HIV infection. Similar to IL-10 and TNF-alpha, IFN-gamma expression was detected in all patients; a peak in the expression of IFN-gamma was observed in five patients with primary HIV infection and in two patients with primary EBV infection. This early peak in IFN-gamma expression coincided with oligoclonal expansions of CD8+ T cells. In this regard, sorted CD8+ T cells from one individual with primary HIV infection expressed significantly higher levels of IFN-gamma than CD8- T cells isolated from the same individual. Sequence analysis of recombinant clones of the expanded Vbeta families during primary EBV infection demonstrated the monoclonal nature of these expansions. These results indicate that high levels of expression of pro-inflammatory cytokines are associated with both HIV and EBV primary infections and that the cytokine response during this phase of infection is strongly influenced by oligoclonal expansions of CD8+ T cells.